Maintaining effective immune surveillance without provoking autoimmune reactions requires the precise titration of effector T cell responses. This fine-tuning may involve the integration of negative or positive signals transduced by inhibitory or activating isoforms, such as the different killer cell Ig-like receptors (KIR), which interact with MHC class I HLA-A, -B, or -C alleles, and the inhibitory CD94-NKG2A and activating CD94-NKG2C heterodimers, which interact with HLA-E. Some of these receptors have the capacity to modulate thresholds of T cell antigen receptor-dependent T cell activation. In the rare absence of inhibitory receptors, the activating isoforms may augment T cell effector functions and contribute to autoimmune pathology.
NKG2D is an activating receptor that interacts with the MHC class I-related MICA and MICB glycoproteins, among other ligands. MICA and MICB have no role in antigen presentation, are generally only found in intestinal epithelium, and can be stress-induced in permissive types of cells by viral and bacterial infections, malignant transformation, and proliferation. NKG2D is a C-type lectin-like activating receptor that signals through the associated DAP10 adaptor protein, which is similar to CD28. It is expressed on most natural killer (NK) cells, CD8 T cells, and T cells, but not, in general, on CD4 T cells. Ligand engagement of NKG2D activates NK cells and potently co-stimulates effector T cells. However, expression of NKG2D is controlled by ligand-induced down-modulation, which is transient and rapidly reversed in the presence of IL-15. Because ligand binding unconditionally triggers NKG2D, its dysregulation together with anomalous expression of MIC in local tissue environments could promote autoreactive T cell stimulation. Other NKG2D ligands include ULBP proteins, e.g., ULBP-1, -2, and -3, originally identified as ligands for the human cytomegalovirus glycoprotein UL16. These proteins are distantly related to MHC class I proteins, but they possess only the a1 and a2 Ig-like domains, and they have no capacity to bind peptide or interact with b2-microglobulin.
Rheumatoid arthritis involves lymphocyte infiltrates, inflammatory mediators, and synovial hyperplasia resulting from aggressive proliferation of fibroblast-like synoviocytes and macrophages. Prognoses of joint erosions and disease severity correlate with high frequencies of clonally expanded CD4+CD28− T cells, which are rare in healthy individuals but occur in other autoimmune disorders. These T cells can be cytotoxic, secrete large amounts of IFN-gamma, and proliferate upon stimulation with autologous adherent mononuclear cells.
Monoclonal antibody-based therapies are now available or in clinical trials for certain diseases, particularly cancers such as non-Hodgkins's lymphoma and breast cancer. The antibodies used in such therapies are generally derived from a non-human animal, and then “humanized” or “chimerized” in order to make them suitable for use in humans. Some monoclonal antibodies are used alone, such as Rituxan (for treatment of non-Hodgkin's lymphoma), Herceptin (for treatment of breast cancer), Campath (for treatment of B-CLL), where they can either slow down or stop the growth of the targeted cells, inhibit their activity, trigger apoptosis, or mark them for destruction by the immune system. In contrast, other antibodies are coupled to toxic moieties, such as radioisotopes, so that they directly kill the targeted cells simply by binding to the targeted receptors. Examples of such antibodies include Zevalin, Bexxar, and Oncolym (all for treatment of non-Hodgkin's lymphoma).